The overall goal of the K02 independent scientist award is to expand Dr. Aghaloo's current research program with (1) formal and informal training in patient-oriented research and statistical methodology, (2) to gain additional knowledge in the basic and clinical sciences of oncology, and (3) to obtain training in proteomics and biomarkers to perform an exploratory patient-oriented study to identify differentially expressed proteins in the saliva of BRONJ patients at different stages of severity. Her current R01 grant focuses on the pathophysiology of bisphosphonate related osteonecrosis of the jaws (BRONJ), by studying both in vitro mechanisms of osteoclast inhibition by bisphosphonates (BPs) and utilizing a clinically relevant in vivo BRONJ animal model. The research strategy in this K02 application will expand those studies with an exploratory study of salivary proteins and peptides to aid in diagnosis, monitoring, and management of BRONJ patients. Intravenous BPs are commonly used medications to treat primary and metastatic bone cancer. Though BPs reduce fracture risk and reduce hypercalcemia of malignancy, many patients develop ONJ. To date, diagnosis of BRONJ has been clinical, often combined with radiographic studies and biopsies to confirm necrotic bone. Therapy ranges from watchful waiting to medical therapy and conservative debridement to hyperbaric oxygen to extensive jaw resection. Outcomes of these treatment modalities are generally assessed by clinical examination, but confusion of continued exposed and necrotic bone vs. delayed wound healing from surgery are challenging to differentiate. In the era of biomarkers, utilizing serum or salivary body fluids is an attractive approach to aid in diagnosis, monitoring, and evaluating responses to treatment. Human plasma and serum is widely used in disease diagnosis, monitoring, and prognosis, and serum profiling has been well documented for various cancers with high sensitivity. More recently, human salivary proteome analysis has been shown to be important for understanding oral health and disease pathogenesis. Therefore, the objective of the research strategy is to identify and validate candidate salivary biomarkers for BRONJ diagnosis, testing the hypothesis that salivary biomarkers are associated with the clinical diagnosis of BRONJ. To achieve our research strategy objective and test our hypothesis, we propose two specific aims: (1) to identify saliva proteins and peptides from cancer patients with Stage I-III BRONJ and (2) to validate proteomics results and develop candidate markers for Stage I-III BRONJ diagnosis. In addition to identifying saliva biomarkers associated with BRONJ, this grant will result in training, hands-on expertise in clinical research, as well as the establishment of an oncology, biomarker, and proteomics infrastructure to allow Dr. Aghaloo to design future clinical studies, whether for ONJ or other oral diseases. PUBLIC HEALTH RELEVANCE: Osteonecrosis of the jaw is a morbid bone disorder associated with bisphosphonate use. Though the incidence is increasing with longer exposure to these medications and comorbidities including chemotherapy, dental disease, and trauma, no validated treatment protocols exist, and many BRONJ patients suffer significant complications including severe pain, swelling, infection, fistulae, and jaw fracture, all of which significantly impact patients'quality of life. Since human plasma/serum has been utilized for many years for cancer diagnosis and prognosis, and human saliva has recently proven to be a valuable diagnostic fluid for other diseases such as HIV, oral cancer, and others, we propose to identify potential biomarker proteins in the saliva of BRONJ patients. Utilizing our basic and translational knowledge of BRONJ and clinical and salivary diagnostic research expertise, our objectives are to improve diagnosis, prevention, and management of BRONJ or patients at risk for BRONJ.